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LEUKOCYTAPHERESIS FOR THE TREATMENT OF
HYPERLEUKOCYTOSIS SECONDARY TO ACUTE
LEUKEMIA
Nicole Aqui, M.D.
Chief, ApheresisServices
Division of Transfusion Medicine
Department of Pathology and Laboratory Medicine
University of Pennsylvania
Learning Objective
• To gain an understanding of the pathophysiology of
leukostasis and the role of leukocytapheresis as a
therapeutic intervention
Hyperleukocytosis
• White blood cell (WBC) count
greater than 100 x 109/L*
• Seen in 5 – 25% of patients with
acute leukemia
• Risk factors include younger
age, certain cytogenetic
abnormalities, and monocytic
differentiation subtypes (acute
myelomonocytic leukemia and
acute monoblastic and
monocytic leukemia)
Mauro MJ. N Engl J Med 2003;349:767-767.
Hyperleukocytosis
• Poor prognosis
• High early mortality
• Lower complete remission rate*
• Decreased disease free survival*
• Can lead to…
• Tumor lysis syndrome
• Disseminated intravascular coagulopathy (DIC)
• Leukostasis
Leukostasis - Pathophysiology
• Multifactorial
• Increased viscosity
• Occlusion of small
vessels by leukemic
blasts
• Tissue infiltration
Lichtman and Rowe, Blood (1982)
*True leukocrit (TRUE) is corrected
for trapped plasma.
*
Leukostasis - Pathophysiology
• AML >> CML, ALL, CLL
• Size of blasts
• Blasts secrete cytokines that increase activation of endothelial cells
and induce adhesion molecules, promoting adhesion of blast cells
to vascular endothelium
• Symptoms can be seen in WBC as low as 50 x 109/L in AML. Often
not seen until > 300 x 109/L in CML, ALL
Leukostasis - Symptoms
• Leukostasis is a clinical diagnosis
• Pulmonary
• Tachypnea, dyspnea, hypoxia
• Neurologic
• Mental status changes, delirium, confusion, headache, dizziness,
tinnitus
• Vascular
• Myocardial ischemia/infarction, priapism, retinal
hemorrhage/thrombosis
Leukostasis – End organ damage
Management of Hyperleukocytosis
• Cytoreduction
• Chemotherapy
• Leukocytapheresis
• Aggressive hydration
• Prevention of tumor lysis syndrome
Leukocytapheresis – Technical Aspects
• Access
• Peripheral
• CVC (preferred) – dialysis-compatible dual or triple lumen
• Medcomp, Quinton Instruments, Hickman
• “Dose”
• 1.5 – 2 blood volumes
• Use pre-, mid-CBC and patient tolerance as a guide
• Frequency
• q12-24 hours
• Treatment of leukostasis: WBC count < 50 x 109/L
• Prophylaxis in asymptomatic patient: WBC count < 50 x 109/L
Side Effects
• Blood loss
• Due to contaminating red cells in buffy coat. The more difficult it is
to obtain interface, the more red cell loss.
• Extracorporeal volume (ECV) varies according to apheresis
instrument, but can be as high as 285 ml
• Transfusions prior to leukocytapheresis may worsen hyperviscosity
(pRBC HCT 60-70%)
• Can give pRBCs as volume replacement at the end of the
procedure
• Platelet loss
• Generally not as severe as RBC loss
Efficacy of Leukocytapheresis • Immediate cytoreduction
• Several studies have shown no effect overall survival
• Conflicting evidence of effect on early mortality
Pastore F, Pastore A, Wittmann G, Hiddemann W, et al. PLoS ONE (2014)
Effect of leukocytapheresis on early death
• Meta-analysis
• 21 studies
• WBC > 100 x 109/L
Oberio et al. Leukemia Research (2014)
Potentially relevant refs
Identified through database
search (n = 5701)
Citations screened by
title/abstract (n = 4876)
Full text refs retrieved for
further evaluation (n = 42)
Studies included in meta-
analysis (n = 21)
Articles excluded (n = 4835)
Excluded (n = 21)
Did not use WBC criteria for
hyperleukocytosis
Selected population
Published < 1980
Did not describe early
mortality
< 5 patients
Publication not in English
Duplicates removed
(n = 825)
Effect of leukocytapheresis on early death
Oberio et al. Leukemia Research (2014)
Subgroups Number of
studies
(patients)
Proportion of
patients with
early death
p value
Leukapheresis 0.67
Universal 5 (157) 25.6
Selected 9 (263) 18.9
Never 1 (45) 17.8
Hydroxyurea/Low
dose chemo
0.23
Universal 8 (430) 22.8
Selected 1 (32) 33.3
Never 2 (278) 10.3
Effect of leukocytapheresis on early death
Study Leukapheresis
Events (Total)
No
Leukapheresis
Events (Total)
Odds Ratio
Bug 2007 4 (25) 9 (28) 0.40
Chang 2007 12 (28) 13 (47) 1.96
Giles 2001 9 (71) 17 (75) 0.50
Inaba 2008 1 (36) 16 (70) 0.10
Sung 2012 1 (16) 3 (73) 1.56
Ventura 1998 7 (61) 10 (24) 0.18
Oberio et al. Leukemia Research (2014)
Role of Leukocytapheresis in APL?
• Acute promyelocytic leukemia with translocation between
chromosomes 15 and 17 (APL), is associated with DIC
and thrombocytopenia, thus these patients are
predisposed to bleeding complications.
• A study to examine treatments for leukocytosis associated
with RA syndrome found that low-dose chemotherapy or
leukapheresis was frequently a trigger event for fatal or
near-fatal hemorrhage. These patients did worse than
those who received no treatment at all. (Vahdat et al, Blood 1994)
ASFA 2013 Guidelines
Indication Condition Recommendation Category
Hyperleukocytosis
secondary to leukemia
Leukostasis Grade 1B I
Prophylaxis Grade 2C III
Conclusions
• Leukostasis secondary to hyperleukocytosis is a
potentially life-threatening complication of acute
leukemias that carries a poor prognosis, thus is a true
emergency.
• The role of leukocytapheresis for cytoreduction is still
unclear. Though patients often experience symptomatic
relief, there appears to be no effect on long-term survival
Conclusions
• The decision to perform leukocytapheresis should in no
way delay more definitive treatment, i.e. hydroxyurea
and chemotherapy.
• In the absence of prospective trials, institutions should
develop their own standardized criteria for the
treatment of asymptomatic patients.
Acknowledgments UPENN Transfusion Medicine Faculty
• Don Siegel, MD PhD
• Una O’Doherty, MD PhD
• Taku Kambayashi, MD PhD
UPENN Transfusion Medicine Staff
• Robin Brown
• Crystal Williamson
UPENN Apheresis Staff
• Leah Irwin, Nurse Manager
• Christa Eisenmann
• Lita Jamensky
• Melissa Murter
• Jane Mason
• Felicia Morrison
• Jennifer Green
• Marcia Hole
• Kevin Schnell
• Karen Fogle